CCX-CKR deficiency alters thymic stroma impairing thymocyte development and promoting autoimmunity

Blood. 2013 Jan 3;121(1):118-28. doi: 10.1182/blood-2012-06-434886. Epub 2012 Nov 14.


The atypical chemokine receptor CCX-CKR regulates bioavailability of CCL19, CCL21, and CCL25, homeostatic chemokines that play crucial roles in thymic lymphopoiesis. Deletion of CCX-CKR results in accelerated experimental autoimmunity induced by immunization. Here we show that CCX-CKR deletion also increases incidence of a spontaneous Sjögren's syndrome-like pathology, characterized by lymphocytic infiltrates in salivary glands and liver of CCX-CKR(-/-) mice, suggestive of a defect in self-tolerance when CCX-CKR is deleted. This prompted detailed examination of the thymus in CCX-CKR(-/-) mice. Negatively selected mature SP cells were less abundant in CCX-CKR(-/-) thymi, yet expansion of both DP and immature SP cells was apparent. Deletion of CCX-CKR also profoundly reduced proportions of DN3 thymocyte precursors and caused DN2 cells to accumulate within the medulla. These effects are likely driven by alterations in thymic stroma as CCX-CKR(-/-) mice have fewer cTECs per thymocyte, and cTECs express the highest level of CCX-CKR in the thymus. A profound decrease in CCL25 within the thymic cortex was observed in CCX-CKR(-/-) thymi, likely accounting for their defects in thymocyte distribution and frequency. These findings identify a novel role for CCX-CKR in regulating cTEC biology, which promotes optimal thymocyte development and selection important for self-tolerant adaptive immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / genetics
  • Adaptive Immunity / immunology
  • Animals
  • Autoimmunity* / genetics
  • Autoimmunity* / immunology
  • Chemokines / metabolism
  • Chemokines, CC / biosynthesis
  • Disease Models, Animal
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Immunophenotyping
  • Kidney / pathology
  • Liver / pathology
  • Lymphopoiesis* / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Receptors, CCR7 / deficiency
  • Receptors, CCR7 / genetics
  • Receptors, Chemokine / deficiency*
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / immunology
  • Receptors, Chemokine / physiology
  • Self Tolerance / genetics
  • Self Tolerance / immunology
  • Sjogren's Syndrome / genetics
  • Sjogren's Syndrome / pathology
  • Stem Cells / classification
  • Stem Cells / metabolism
  • Stem Cells / pathology
  • Submandibular Gland / pathology
  • Thymocytes / pathology*
  • Thymus Gland / pathology*


  • Ackr2 protein, mouse
  • Ccl25 protein, mouse
  • Ccr7 protein, mouse
  • Chemokines
  • Chemokines, CC
  • Receptors, CCR7
  • Receptors, Chemokine